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InsideHealthPolicy.com’s
FDA Week
an exclusive weekly report on Food and Drug Administration policy, regulation and enforcement
Vol. 21, No. 11 — March 20, 2015
Court Rules Biosimilar Applicants Don’t Have To Engage In Patent Dance
The U.S. District Court of the Northern District of California ruled in Sandoz’s favor Thursday (March 19), saying
that a biosimilar applicant is not required to undergo a so-called patent dance where they provide their manufacturing
information to the reference product sponsor, and that the decision not to partake in the patent dance does not offer a
basis for the sponsor to obtain injunctive relief, restitution or damages against the applicant. The court also ruled “there
exists no substantive bar to market entry for Sandoz’s biosimilar filgrastim,” rejecting brand maker Amgen’s efforts to
delay marketing of the biosimilar.
continued on page 15
Senate Staff Working Group Moving Toward ‘Alternative’ Cures Bill
A Senate health committee staff working group that convened last month is moving to create its own version of the
House proposed 21st Century Cures bill, dubbed the “alternative,” sources with knowledge of the working group said.
The drafting approach differs greatly from that of the House, with the Senate working group bringing in top FDA and
National Institutes of Health officials on a regular basis over the next several weeks to eventually make policy recommendations to their respective senators, sources said.
Some consumer advocates have criticized the House approach as not considering agencies’ concerns and needs, but
continued on page 6
FDA Drug Safety-Related Needs Reflect Hamburg Comments, ‘Cures’ Draft
FDA detailed seven areas as drug safety-related regulatory science needs, including the development of clinical
biomarkers for safety, that would benefit from additional resources and collaboration in a report the agency released
Thursday (March 19). This follows a push by outgoing Commissioner Margaret Hamburg for lawmakers not to lower
the safety and efficacy standards by which the agency assesses treatments.
The report reflects work done by FDA drug center’s Safety Research Interest Group that identified seven areas of
safety-related needs, and identified particular priority projects requiring additional resources and collaboration.
continued on page 9
Public Citizen: Stakeholders Pan FDA Plan To Let Rx Makers Downplay Risks
Public Citizen says more than 99 percent of those commenting came out against an FDA draft guidance that would
allow drug manufacturers to present materials to doctors that show the risks of a product are lower than those detailed
on an official label. The watchdog group wrote to FDA last Wednesday (March 11) urging it to immediately withdraw
the guidance, arguing that if finalized the document would undermine the benefit-risk balance in the new drug application process in a way that favors drug companies and could harm patients.
Public Citizen says it discovered through a Freedom of Information Act request that only 11 of the 1,782 comments
continued on page 11
Drug Safety Advocates Want Bioequivalence Data To Be Made Public
A group of drug safety advocates are pushing for FDA to make its bioequivalence data available so that physicians,
pharmacists, researchers and buyers can see how the agency makes such determinations, which they say can result in a
large difference between the amount of active ingredient an innovator product and a generic drug version deliver to a
patient, according to a working paper the advocates unveiled Wednesday (March 18). The advocates also touch upon
challenges that FDA may face in determining therapeutic equivalence for the upcoming wave of biosimilar products.
The Searching for Safety group — whose mission is to address the scientific, legal and socioeconomic
continued on next page
analysis of dangerous products, who makes them, trades them and how prevalent they are — released a working
paper “Drug Inequality: Allowable variations and illegal underperformance in off-patent drugs” and held a Senate
briefing Wednesday.
Roger Bate, an adjunct scholar at American Enterprise Institute, director of the Safe Medicines Coalition and
SearchingForSafety.net, told Inside Health Policy that the group is speaking with the Senate health committee and the
House Committee on Ways and Means on these issues.
The working paper discusses the range of variation in the amount of active ingredient delivered to a patient between
innovator drugs and generic drugs, which they say is between 80 percent and 125 percent of the drug in blood plasma
over time. This variation the report says can be too broad for some drugs, such as post-transplant immunosuppression
where minor variations in a drug might lead to organ rejection. Additionally, the paper states that two generic drugs that
are deemed bioequivalent to the innovator product may not be “bioequivalent to each other, which might cause additional
problems.”
“One might hope that the FDA would recognize the need for narrower bioequivalence ranges for certain
drugs... Rumors are circulating that FDA is considering tightening BE standards for narrow therapeutic drugs,” states the
report.
The group continues to say that the only way they could trust FDA’s bioequivalence assessment process is if the
agency release bioequivalence curves and absorption data. This effort is reflected in a recent New York state legislation
that would require generic drug manufacturers to make bioequivalence data and incidence of adverse events available so
it can be published publicly.
The paper recommends that the agency immediately publish all bioequivalence data, starting with narrow therapeutic
and time release medicines; require that dispensed generic drugs identify manufacturer or distributor; and increase
transparency by posting detailed metrics and compliance data from Establish Inspection Reports, Form 483s, Warning
Letters and other OAI actions.
The group also advocates increased authority for FDA to block the importation of products from foreign companies
with a history in the last 10 years of quality problems and are being investigated for additional compliance related
problems; and it also calls for increased market surveillance.
The problems that were raised in the paper will be exacerbated by biosimilars, the advocates say. “They are
more expensive to create — and arguably far more difficult to regulate.”
The paper references an estimate by the OMICS Group that said India and China are poised to take over much
of the biosimilar production lines, potentially commanding as much as 70 percent of the global market over the next
few years.
“Establishing therapeutic equivalence in the case of biosimilars presents a challenging problem,” states the
paper. “Yet none of the India or Chinese based manufacturers have conducted a pivotal clinical study for a new
molecule outside of India/China. Their ability to properly plan and conduct clinical studies to demonstrate therapeutic equivalence and provide reproducible results which can be replicated in the western world is yet to be established.”
The group recommends that the National Institutes of Health fund the development of characterization kits to help
importers quickly assess the purity, conformation of the protein and its activity before the product can be allowed to enter
the U.S. market.
The research was funded by the International Policy Network and the American Enterprise Institute.— Erin Durkin
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FDA Week - www.InsideHealthPolicy.com - March 20, 2015
Bipartisan Policy Center Launches FDA-Focused Medical Innovation Effort
As the Bipartisan Policy Center (BPC) this week launched its own medical innovation initiative, medical product
experts, including a former FDA commissioner, said Congress, the White House and FDA should look to increase the
patient perspective in innovative research and realign the incentive structure to encourage industry to pursue treatments
earlier in the disease cycle in areas like cancer. BPC is looking at the issue with a focus on FDA as the House, Senate and
Obama administration each pursue efforts focusing on spurring medical innovation and precision medicine. The BPC said
it hopes to issue a white paper on ideas it thinks Congress and the administration should pursue in late-spring or earlysummer.
Former Sen. Bill Frist (R-TN), who chairs BPC’s Advancing Medical Innovation Through Public Policy Initiative,
said the time is right for stakeholders and Congress to find ways to ensure the U.S. continues lead the world in medical
innovation, adding the cost to develop a new drug or device is skyrocketing and venture capital for medical innovation is
fleeing overseas. He said he is buoyed by the bipartisan congressional efforts: House Energy and Commerce Committee
chair Fred Upton (R-MI) and Rep. Diana DeGette (D-CO) are spearheading a 21st Century Cures initiative, and Senate
health committee chair Lamar Alexander (R-TN) and Sen. Patty Murray (D-WA) are working on a parallel Innovation for
Healthier Americans initiative.
“For me it’s very energizing and makes me very optimistic is that this is strictly a bipartisan issue,” Frist said. “There
will be little angles from either side with a little nuance, but at the gist and at the heart, and at really what is important
substantively there is huge bipartisan support.”
In a panel discussion moderated by Frist at BPC’s launch of the initiative Monday (March 16), Marc Boutin, CEO of
the National Health Council, said one of the most important things that can be done is to more fully incorporate the
patient perspective into manufacturers’ development processes and FDA’s regulatory process. Boutin said integrating
patients into the process began with provisions of the Prescription Drug User Fee Act reauthorization in 2012, and FDA
has followed up with a series of meetings with patients’ groups, but more needs to be done especially in the area of
benefit-risk analysis.
Boutin said the FDA meetings led to many “aha” moments for officials, because the goals and needs of patients are not always the same as regulators and drug and device developers. Patients, he said, make decisions based
on their life goals and how a disease needs to be treated and manged for them to meet those goals.
One of the problems he said is that the development process has been professionalized in a way that separates
developers and researchers from patients. Boutin said 20 years ago many of the people conducting research were clinicians who had experience with patients, and now research is dominated by Ph.Ds who have had limited contact with
them.
“There’s a lot of scientific data, but at the end of the day when you’re making a decision on benefits and risk it’s a
judgment; it is not science,” Boutin said. “And your making your judgment on behalf of everybody that’s going to
potentially take that medicine. That’s huge; that needs to reflect the end user. And in many instances the people making
that decision have not been informed by the end user.”
Boutin said Congress and FDA should use this opportunity to set in place “guardrails” that can guide the agency and
industry on ways to fully incorporate the patient perspective into the development process.
He also said that the incentive scheme, using such things as exclusivity for drugs and devices, needs to be
reworked so that companies pursue treatments for things like early-stage cancer. He said the way incentives work now,
most companies go for the low hanging fruit that leads to exclusivity for treatments with things like late-stage cancer.
“I don’t have the specific examples of how we solve this, but we as a society 30 years after the last time we looked at
this have to have a discussion about what do we want to incentivize,” Boutin said. “Treatments for people who have four
months to live with cancer is not necessarily a bad thing, but would it not be better to develop treatments that prevent
cancer. These are all initiatives that we can change as a society.”
A discussion draft of Upton’s 21st Century Cures legislation includes provisions that would expand exclusivity in a
number of areas, including 15 years of exclusivity for “dormant therapies.” The provisions have garnered a chilly
reception from the generic drug lobby, which argues that increased exclusivity keeps patients from accessing cheaper
generic versions sooner.
“GPhA strongly supports the intent of the 21st Century Cures initiative. The balance between creating competition
and encouraging innovation is essential and has been vital to breakthroughs in medicine since the enactment of the 1984
Hatch-Waxman law,” said Ralph Neas, president and CEO of the Generic Pharmaceutical Association, in a statement to
FDA Week Thursday (March 19). “However, the Dormant Therapies provision would grant brand drug companies an
unprecedented increase in exclusivity for an undefined and broad category of new drugs — delaying competition from
generic drugs and biosimilars while hindering access to medicine for millions of people and putting billions of dollars in
savings at risk.”
Mark McClellan, senior fellow and director of the Health Care Innovation Value Initiative at the Brookings Institution and former FDA commissioner, echoed Boutin’s statements during the panel discussion and said FDA has been
FDA Week - www.InsideHealthPolicy.com - March 20, 2015
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pursuing a number of ideas being discussed in Congress. McClellan said not only does FDA need more resources to deal
with the expansion of its mandates in recent years, it also needs to be unshackled in a way that lets it more fully pursue
innovative ways to get drugs and devices through the process and encourage industry to do things like incorporating more
patient perspectives in their processes.
He said one way to get more patient input is allow FDA to access patient feedback gathered by hospitals and
health plans as part of cost control and value reform efforts set up by the Affordable Care Act.
“Now in 2015 some of the best best opportunities to do that can certainly come with more resources for the agency,
but can also come from more support for collaborations with health plans, with health care organizations that are collecting more comprehensive longitudinal data on patients,” McClellan said. “That’s what a lot of the payment reforms
that are taking place in health care now are all about. It’s not about how many treatments you got, but it’s about
what’s really making a difference for the health of each individual that’s getting surgery, that’s in an accountable
care organization or something like that. So lots more opportunities to bring in data.... What we don’t have yet is
ways to approach that.”
Frist and his co-chair of the BPC initiative former Rep. Burt Gordon (D-TN) also stressed that safety and
effectiveness were top priorities for any efforts to streamline the process to spur innovation, and both expressed
confidence that the members of Congress leading the initiatives will come up with workable bipartisan measures.
“With these serious legislators trying to work together it’s just like slopping the trough,” Burton said. “When you
bring them some good ideas, you know, that’s what they want. So we’re going to bring them good ideas and let them go to
the trough.”
Frist said BPC plans to release a white paper with specific ideas and recommendations in late-spring or early
summer. — Todd Allen Wilson
Hamburg Echoes Consumers’ Concerns With Lowering FDA Standards
Outgoing Commissioner Margaret Hamburg countered what she said were common “misconceptions” about FDA
when she appeared before the Senate health committee last week, defending the agency’s gold standard for drug approval
and echoing consumer advocates’ contention that those pushing to overhaul the clinical trial process are relying on
erroneous complaints. Consumer and research advocates recently urged the Senate health committee to go back to the
drawing board on its Innovation for Healthier Americans initiative to focus on product safety and effectiveness, and have
raised similar concerns with the House’s parallel 21st Century Cures effort.
Hamburg, who is expected to step down at the end of March, likewise made a push for lawmakers to focus on FDA’s
safety and effectiveness standards, and countered suggestions that the agency is an obstacle to the marketing of new
drugs.
“I cite these examples to suggest not that the world of biomedical research and product development is all fine, but to
urge that we start with the right diagnosis,” she told lawmakers at the first Senate health committee hearing on its new
innovation effort. “We do not want solutions based on inaccurate diagnoses. I caution against solutions that seek to lower
the safety and effectiveness standards for approval of the medical products on which Americans rely.”
The first “misconception” cited by Hamburg is the repeated assertion that FDA’s approval of new drugs lags
behind other countries. She said that in reality over 75 percent of the new drugs approved by Japan, the EU, Canada,
Australia and Switzerland between 2004 and 2013 were first approved by FDA, referencing a report by the Centre for
Innovation in Regulatory Science.
Second, she countered suggestions FDA is rigid and inflexible in its approach to requesting and using data for
approval of a new drug. Instead, she said, FDA’s clinical trial requirements have become more flexible. She notes that
45 percent of new drugs are approved based on a surrogate endpoint, one-third are approved on the basis of a single
clinical trial, and the agency last year used the expedited approval processes for more drugs than it had in the past.
Third, Hamburg debunked assertions that U.S. investment in biotechnology has dropped due in part to FDA
policies. She referenced data from the National Venture Capital Association showing that biotechnology investment
dollars rose 29 percent in 2014 to $6 billion, placing it as the second largest investment sector for the year in terms of
dollars invested.
Hamburg’s counterpoints are similar to those raised recently by a coalition of patient, consumer and public health
advocates in a letter urging Senate health committee Chair Lamar Alexander (R-TN) to go back to the drawing board on
his innovation plan. [82160]
The Patient, Consumer, and Public Health Coalition (PCPHC) recently wrote to Alexander that it disagreed
with the following key tenets of his innovation white paper:
It costs companies too much to bring products to market.
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FDA Week - www.InsideHealthPolicy.com - March 20, 2015
FDA review delays are impeding innovation.
Entitlement spending is cutting into medical research.
Flexible and adaptive trials are good for industry.
Greater reliance on post-market studies for devices and drugs is good for patients.
FDA should harmonize its regulations with those of other countries.
The coalition made the following points in its letter to Alexander:
Over the past two years, pharmaceutical company device manufacturer stocks have out-performed NASDAQ
and the New Your Stock Exchange and that device makers profit margins have “remained very strong and
steady” over the last decade.
Data show the average FDA review time for a new drug application has gone down from more than 30 months
in the 1980s to 9.9 months in 2011.
Alexander creates a “false and dangerous dichotomy” when he states in the white paper that the decline in
National Institutes of Health purchasing power is in part because of “entitlement spending.” The coalition
says spending on programs such as Medicaid and Medicare has actually increased the revenues for pharmaceutical companies and medical device companies.
A lot more flexibility from FDA on clinical trials would be bad for companies that need predictability.
To protect patients, medical products should be shown to be safe and effective before they are marketed.
FDA has some of the highest regulatory standards and harmonization would lower standards, thereby lowering the safety and effectiveness of drugs and devices.
“Congress clearly does not have the expertise needed to advise the FDA or NIH about the appropriate design of
clinical trials,” Diana Zuckerman, president of the National Center for Health Research, said in a statement to FDA
Week.“The 21st Century Cures paper reflects the goals of venture capitalists, pharmaceutical companies, and patient
groups funded by pharmaceutical companies, rather than the goals of medical experts and public health advocates.
Congressional efforts to make the process less burdensome for companies is making it more burdensome for
patients and doctors. In the absence of large, well-designed clinical trials, physicians (and their patients) need to
choose treatments that are not proven safe or effective for most patients. This white paper would make that situation
even worse.”— Erin Durkin
FDA Takes Neutral Stance In NY AG Dietary Supplements Bout
FDA expressed in a letter to senators that it neither condones nor finds inappropriate a certain DNA barcoding test
used by New York Attorney General Eric Schneiderman to determine some dietary supplements in his state were adulterated or contained undeclared ingredients. The letter was in response to a February inquiry from the Senate Dietary
Supplements Caucus chairmen Martin Heinrich (D-NM) and Orrin Hatch (R-UT) on whether the DNA barcoding test is
recommended by the agency.
FDA Associate Commissioner for Legislation Thomas Kraus said the agency currently does not use DNA-sequencing
tests for plant identification. “FDA has validated a DNA barcoding method for seafood species identification that is
currently being used by FDA and other agencies and is posted for public access,” said Kraus in the letter. “Currently, if
FDA were to use DNA methods on botanical extracts, we would use them in combination with established chemical or
other acceptable methods historically used to verify the identity of these products.”
Kraus also said the agency has not received the testing methodology or results from Schneiderman’s office and could
not “address the validity of the the results.”
The agency’s response to the pair of senators comes as Schneiderman ordered dietary supplement retailers GNC,
Target, Walgreens and Walmart to pull some supplements off the shelves because the AG’s office found some ingredients
were undeclared in the pills’ labels. Schneiderman issued cease and desist letters after using the controversial DNA
barcoding for his office’s findings.
GNC conducted its own tests and commissioned another by a third-party and found its products to be pure, according
to a press release, and announced it would return its products to the shelves. At the same time, the dietary supplements
lobby issued a white paper criticizing Schneiderman’s use of the DNA barcoding test, saying that it is a faulty test to use
on botanical products.
The senators asked FDA directly if it recommended the use of the test to confirm the identity of key chemicals found
in herbal extract dietary supplements. The agency’s response: “At this time, FDA does not use DNA sequencing by itself
to analyze an herbal extract for phytochemicals.” — David Hood
FDA Week - www.InsideHealthPolicy.com - March 20, 2015
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Working Group Seeks ‘Cures’ Alternative . . . begins on page one
instead letting industry dictate the terms of the draft bill released in January. Industry will get its turn to talk to the
bipartisan Senate working group in person, but only after agencies have had the opportunity to weigh in, sources said.
The idea, sources said, is to start a bill from scratch with the goal of a bill in the upper chamber by year’s end.
Tennessee GOP senator and Chairman of the Senate health committee, Lamar Alexander, released a white paper asking
industry for input at the same time the House 21st Century Cures draft bill was introduced, with a lot of the same ideas
represented in both. The Senate draft, sources said, will reflect what the Senate aims to do rather than a fix of the House’s
version.
“While the goals of the House and Senate may remain the same, to ensure that our resources and funding are used in
the most efficient way possible — so that researchers are equipped to make discoveries that will lead to the development
of appropriate treatments and medical devices — the Senate aims to find simple, yet comprehensive solutions to these
problems,” one source told FDA Week in an interview on the condition of anonymity. “Likely, by aiming to address a few
key areas needing reform versus the entire overhaul offered by the House.”
But sources say the Senate workgroup is intentionally leaving out House members and their staffs as it directly meets
with agency representatives, including some top officials like Jeff Shuren, director of FDA’s device center.
In those meetings, staff members asked agency officials what would make their jobs easier or what their legislators
could do. The response: more funding for FDA so staffs could be increased to effectively take on the increasing workload
Congress imposes on the agency every year with new legislation giving the agency more responsibilities without more
resources.
In the most recent hearing, outgoing FDA Commissioner Margaret Hamburg appealed to Senate health panel members to make “appropriate investments” in FDA, along with investments to the National Institutes of Health, to give the
agency opportunities to develop “areas of science.”
The Senate working group has no hard deadline to collect information for policy recommendations that will eventually make their way into a bill. In the meantime, three hearings on health-related issues will be hosted by the committee as
a kind of pincer move, gathering information from members and from their staffs.
“Instead of reviewing feedback from just the industry, HELP has brought agencies and other key stakeholders into
the discussion. The Innovation Report was the first step in that process. The working group and hearings are the second,”
the source said. — David Hood
Public Citizen Urges FDA To Reject Asthma Combination Therapy
Public health advocate Public Citizen urged FDA not to approve a combination therapy for asthma that the group
says could be dangerous to younger consumers because little is known about the medicine even in adults. The group
raised the issue at FDA’s Pulmonary and Allergy Diseases Advisory Committee meeting Thursday (March 19). The
advisory committee recommended approval use for adults at the meeting.
The therapy in question, Breo Ellipta, “offers no unique advantages over currently available long-acting beta agonist
(LABA) asthma therapies, and has not undergone a large enough clinical trial to ensure that it does not worsen asthma
outcomes, the condition it is supposed to treat,” said Sammy Almashat, a researcher with Public Citizen’s Health Research Group, in a statement. “There is no reason to approve a ‘me-too’ medication before such a trial sheds more light
on its potentially life-threatening risks.”
The group cited studies that show giving asthma patients a LABA-containing medicine increases the risk of asthmarelated hospitalizations and deaths. In 2011, FDA required manufacturers of LABA-containing asthma medications to
conduct postmarket studies to determine safety and effectiveness. The results of those tests are expected by 2017.
At the same time, FDA issued a warning to consumers not to rely on over-the-counter asthma products labeled as
homeopathic as those products have not been approved by the agency for safety and effectiveness. — David Hood
EPA Allows FDA Access To Data On Chemicals In Foods, Feed
Through a memorandum of understanding, the Environmental Protection Agency will now allow FDA access to
information on chemicals that may be present in foods, according to a Federal Register notice posted Monday (March
16). FDA requested access to information collected by EPA under the Toxic Substances Control Act (TCSA) and Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) a year ago and was granted permission by EPA in the memorandum.
EPA will also benefit from the information-sharing agreement. Since FDA regulates food safety and animal feed
regulations, it has access to critical information about the toxicity of pesticides and other chemicals used that may come
in contact with food and feed. The information-sharing is supposed to provide updated data and assist in coordinating
reviews between agencies.
Ricardo Carvajal, a former FDA associate chief council and now a director at Hyman, Phelps & McNamara, said the
document will not change any standards or regulations on the FDA-side of the memorandum, but will result in more
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FDA Week - www.InsideHealthPolicy.com - March 20, 2015
information for the two agencies that should help them better do their jobs.
“I don’t think we’re going to see a change in standards that are applied or the process that the agencies follow,” said
Carvajal. “If you step back to think about it, from their perspective, it would seem a little dysfunctional if there’s one
agency in the federal government that is making a decision on safety on the proposed use of a substance and there’s
another agency in the federal government that has information in its files that’s relevant to the determination of safety, and
there’s no mechanism for accessing that information.”
The document explains that some situations arise where a substance used in crops may be regulated by both
agencies. The information-sharing will also help the agencies better analyze the chemicals.
“The expectation is that the two agencies will share, on a reciprocal and as-needed basis, information, including nonpublic information, which may facilitate implementation of the agencies’ respective programs,” the notice says. “This
activity is intended to maximize the utility of data collected under those statutes, and enhance the efficiency of the
participants’ regulatory processes and facilitate better risk management activities.”
Some information, classified as Confidential Business Information or proprietary information about private business
practices, will be provided to FDA on a ‘need-to-know’ basis, according to the notice.
“It’s not as if industry has a lot of choice,” said Carvajal. ”The agencies have the authority to set up this framework
for the sharing of information subject to all these controls and the penalties that they would be subject to if they don’t
follow those controls should be enough to make sure that everybody’s careful. Now, can mistakes happen? Sure,” said
Carvajal, noting that the important part is how the controls are set up. — David Hood
Korea Accuses U.S. Of Failing To Provide ‘Patent Linkage’ For Biologics
South Korea is arguing that the U.S. marketing approval system for biologic drugs might not comply with the
intellectual property (IP) provisions of the Korea-U.S. Free Trade Agreement (KORUS) as a way of deflecting U.S.
complaints about Seoul’s implementation of a “patent linkage” system to comply with the pact.
Seoul’s claim hinges on the notion that the United States has created what Korea sees as a “bifurcated” system for
patent linkage for two different classes of drugs: biologic drugs — which are regulated by the Biologics Price Competition and Innovation Act (BPCIA), part of the larger health care law that Congress passed in 2010 — and small-molecule
drugs, which are regulated by the Hatch-Waxman Act of 1984.
Both laws contain measures aimed at preventing the approval of generic drugs that infringe on existing, valid patents.
But the system under the BPCIA is fundamentally different in key ways compared to Hatch-Waxman, which the U.S.
brand name drug industry usually points to when describing how patent linkage should work.
The Korean National Assembly earlier this month passed legislation that creates a new Hatch-Waxman style patent
linkage system that applies universally to both small molecule and biologics drugs, in order to comply with an obligation
under KORUS to do so by year three of the agreement’s entry into force, which was March 15. But in the run-up to its
enactment, Korean opposition lawmakers floated the possibility of carving out biologic drugs from this new system.
Seoul publicly raised the issue in a February 13 submission to the Office of the U.S. Trade Representative, as part of
USTR’s annual “Special 301” review of trading partners’ IP policies. Specifically, Korea was responding to a complaint
lodged by the Biotechnology Industry Organization (BIO) about a Korean opposition party-sponsored amendment that it
said raised “concerns” in the U.S. that biopharmaceuticals would be excluded from patent linkage.
Korea has not indicated any offensive commercial interest in the biologics patent linkage issue, except as a rebuttal to
these arguments. Korea’s drug industry is heavily dominated by generics manufacturers.
“As the proposed bill excluding biological pharmaceuticals is pending in the National Assembly, the government is
working to ensure the inclusion of biological pharmaceuticals,” Korea said in the submission. “However, the Korean side
believes that the U.S. side needs to prove that the U.S. system related to biological pharmaceuticals completely complies
with the KORUS FTA.”
In a Feb. 17 letter to Korean Minister for Food and Drug Safety Chung Seung, U.S. Ambassador to Korea Mark
Lippert fought back against Seoul’s claims. The letter, published on the website Heesob’s IP Blog, references a conversation the two officials had regarding Korea’s patent linkage obligations under KORUS and attempts to clarify the U.S.
definition of patent linkage.
“[I] would like to assure you that KORUS patent linkage obligations cover all pharmaceutical products, including
biologics, as set forth in the agreement,” Lippert said in his letter. “The United States meets this obligation through the
Hatch Waxman Act and the Biologics Price Competition and Innovation Act (BPCIA), and the U.S. system therefore is
KORUS-consistent.”
Lippert raised the issue both in the context of KORUS and the Trans-Pacific Partnership (TPP) — which Korea had
indicated a preliminary interest in joining — noting that the U.S. is seeking to include similar obligations in TPP. He
mentioned the importance of patent linkage for biologics innovators and its connection to both agreements.
“While we appreciate the hard work by your government to develop a patent linkage system in time for the March
15, 2015 KORUS deadline, I would also like to reaffirm that it is critical that Korea adopts a patent linkage system that
FDA Week - www.InsideHealthPolicy.com - March 20, 2015
7
covers all pharmaceutical products, in line with KORUS,” he said.
An informed source said following the date the letter was sent that he was not aware of any understanding between
the two governments that had resolved the issue. He said working-level officials are continuing to hold discussions, but
that these talks have not done anything to convince Seoul that the BPCIA should be considered part of the U.S. patent
linkage regime.
The U.S. government and pharmaceutical industry have also objected to the way Seoul plans to implement aspects of
its newly passed patent linkage law and a separate proposal to reclaim profits gained by brand name drug companies that
ultimately lose their patent suits.
Korea’s new patent linkage system is modeled on Hatch-Waxman, the guiding statute in the U.S. Food and Drug
Administration’s (FDA) enforcement of the U.S. patent linkage system.
Under Hatch-Waxman, a generic company must inform the holder of the relevant patent before the FDA grants
marketing approval to a new follow-on generic drug. If the patent holder objects — by claiming that the patent is still
valid, for example — FDA grants an automatic stay of 30 months to allow the matter to be litigated.
The new South Korean system works in much the same way, although its stay period is only nine months long and the
same obligations apply for both traditional small-molecule drugs and biologic medicines.
In the U.S., however, the system for approving generic biologics drugs — called “biosimilars” — is dictated by the
BPCIA and functions much differently than Hatch-Waxman.
Specifically, the BPCIA does not require that a biologics patent holder be notified if a biosimilar manufacturer
applies for a marketing approval of a biosimilar that could infringe the innovator’s patent, nor does the FDA issue a 30month stay of marketing approval if a patent holder objects, according to a patent lawyer.
Instead the BPCIA requires the patent holder, or “reference product sponsor,” and the biosimilar applicant to enter
into negotiations between themselves over whether an existing, valid patent is infringed. This process — which the lawyer
dubbed the “patent dance” — sets up three 60-day periods during which the two parties exchange offers on which patents
are relevant to the pending biosimilar application, and thus could be challenged in a court.
Following these exchanges, the law gives the parties an additional 15 days to reach an agreement on the application
before the brand-name manufacturer can pursue litigation. In lieu of an automatic stay, the brand-name manufacturer can
ask the court hearing the litigation for an injunction against marketing approval of the generic.
The patent lawyer noted that the BPCIA process has not been extensively litigated because of the statute’s young age
and because the requirements and deadlines during the negotiations have had a chilling effect on biosimilar applications;
the first biosimilar drug in the U.S. was approved earlier this month.
One outstanding issue under the BPCIA is whether the generic company can refuse to enter into negotiations over the
relevant patent, leaving an innovator company with the choice of moving directly to litigation. A case pending in the
Northern District of California — between brand-name company Amgen and generics firm Sandoz — is currently
examining whether Sandoz is able to bypass the “patent dance.”
The patent lawyer said that if Korea’s main complaint is that the U.S. patent linkage system for biologics is that it is
not similar to Hatch-Waxman, then Seoul has a legitimate point. But he also argued that the KORUS language is vague
enough to include the BPCIA system within its scope, and thus can be considered patent linkage.
That provision, KORUS Article 18.9.5, states that parties shall “implement measures in its marketing approval
process to prevent such other persons from marketing a product without the consent or acquiescence of the patent owner
during the term of a patent notified to the approving authority as covering that product or its approved method of use.”
Although Lippert raised patent linkage for biologics in the context of TPP, one industry source said he was not aware
of any countries currently negotiating TPP raising the same complaints as Seoul in their IP negotiations with the U.S. He
also said that if USTR took seriously the claim that the BPCIA does not constitute patent linkage for biologics, the agency
would have notified Congress that the validity of an existing U.S. statute was in question.
“You can be confident that USTR is not negotiating provisions that would compel changes to biologics,” this source
said. USTR did not respond to a request for comment. — Inside U.S. Trade
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FDA Week - www.InsideHealthPolicy.com - March 20, 2015
FDA Names Drug Safety Science Needs . . . begins on page one
One area FDA is looking at is the need to investigate clinical biomarkers of safety, including standards for qualification. This would include exploring differences between evidentiary standards for nonclinical and clinical biomarkers;
developing a framework for an objective cost-benefit model to evaluate and prioritize biomarkers to pursue for qualification and facilitate discussion regarding whether existing biomarkers can answer the most critical questions and whether
additional biomarkers are needed; and developing a more integrative strategy of biomarker development.
This echoes comments made by Hamburg to lawmakers at a Senate health committee hearing last week
against solutions that would lower safety and effectiveness standards” for approval of the medical products on
which Americans rely.” Instead, she recommended lawmakers focus on incorporating scientific, disease-based patient
input in the development and review process; providing more attention to the development of biomarkers; developing
methodologies to harness real-world data; and ensuring FDA can attract and retain scientists.
Another area of interest reflects provisions included in the House Energy and Commerce’s 21st Century Cures draft
bill. Specifically, lawmakers include language that calls on FDA to develop guidance and regulations that allow clinical
trial sponsors to propose adaptive and alternative trial designs, which includes the use of Bayesian methods — a form of
statistical design that relies on probability distributions that use sequential analysis techniques that include outcomes of
previous experiments in designing new experiments.
FDA says in the report that it is looking to improve clinical trial statistical analyses for safety, including benefit-risk
assessment by identifying scenarios where the application of Bayesian methods can enhance the content of targeted
statistical safety reviews and apply these methods to safety data from randomized clinical trials.
The agency also aims to improve access to postmarket data sources and explore the practicability of their use in
safety signal analyses. FDA further elaborated on the research activities, which includes improving tools for conducting
postmarketing safety surveillance by support the Innovation in Medical Evidence Development and Surveillance;
evaluating overall utility and practicality of product-specific registries; and determining appropriate data sources for
determining “suicidality” in populations of interest.
The next area looks to improve risk assessment and management strategies to reinforce the safe use of drugs by
evaluating the effectiveness of various methodologies used as part of risk evaluation and mitigation strategy (REMS)
assessments; developing innovative methods to create, facilitate and encourage research in the area of safe medication
use; and collaborating with local and state health departments to help identify high-risk and unapproved finished drug
products to establish a list of target products.
Additionally, FDA identifies the need to evaluate the effectiveness of risk communications of drug safety
information to health care providers and the public. Activities in this area would require investigating the most
appropriate measures for determining the impact of FDA’s drug center Drug Safety Communications; investigating,
analyzing and communicating the most effective approaches to reduce preventable harm from certain drugs, such as
opioids; and determining the most appropriate way to communicate with consumers about the safety and effectiveness of
generic drugs and biosimilars, given current public perception.
FDA is also seeking to improve product quality and design, manufacturing processes and product performance
relating to safety by determining what data are needed to decide whether a postmarket adverse event is caused by a
product quality issue; by developing advanced methods to evaluate the effect of product quality factors of biosimilars on
clinical pharmacology and safety; and by advancing the methodology for antibody-drug conjugate products to determine
the distribution of a drug and drug-linked antibody.
Finally, the agency names the need to develop and improve predictive models of safety in humans, including
nonclinical biomarkers, echoing remarks by Hamburg as an area to pay attention to. This would involve developing a
general framework to support a systems pharmacology approach that leverages laboratory results, published data and
computational modeling to evaluate drug safety. — Erin Durkin
Stakeholders Float Ways To Speed FDA Development Of Final Guidance
Industry stakeholders are urging FDA to use digital tools, including live chat and phone support, to speed the
availability of final policy guidance — a move they say would make agency guidance more useful in the regulatory
process. The ideas, some of which were outlined in recommendations sent to FDA late last year, come as Senate health
committee’s new efforts to address the agency’s heavy reliance on draft versions of guidance as part of the panel’s
Innovation for Healthier Americans effort.
The Combination Products Coalition sent recommendations to FDA last October for streamlining the guidance
development process and curtailing the agency’s reliance on draft guidance.
The Senate health committee, as part of its parallel initiative to the House’s 21st Century Cures Initiative, recently
sought input from stakeholders on FDA’s strong reliance on draft guidance and its slowness in completing final versions
of the documents. Committee members criticized the large number of outstanding draft guidances and FDA’s alleged
FDA Week - www.InsideHealthPolicy.com - March 20, 2015
9
reliance upon them at a hearing last week.
Bradley Thompson, an attorney at Epstein Becker & Green, said that FDA allegedly uses guidance documents as a
less onerous form of rulemaking, and knowledge transfer, but he says the agency “is failing in both cases.”
“It has gotten so complicated and bureaucratic and constipated that it takes years to write a draft guidance, a draft that lacks
public input and that frankly never gets substantially revised if it ever gets finalized,” said Thompson. “Further, these guidances
ossify — stagnating because the process of updating them is so burdensome and time-consuming. Basically the flow of
information — both high-level important policy and low-level but still important data points — has slowed to a trickle.”
He further states that FDA is putting stakeholders in a position where if they want more guidance in an area, they
have to accept that more guidance will likely not be finalized, adding that in order for the agency to do more would
require FDA getting more resources.
Thompson described a legislative solution that leverages digital tools, such as: help pages, frequently asked
questions, searchable knowledge bases and community forums, along with live chat and phone support.
In October, the Combination Products Coalition — for which Thompson serves as general counsel — sent FDA
recommendations to improve its good guidance practices. The coalition urged FDA to:
Ensure the scope of a guidance is not broader than the title suggests.
Before drafting a guidance, solicit input from stakeholders on the key questions they would like to see answered in
the guidance document.
Adopt a defined pathway for the public to propose guidance documents.
Improve the guidance development process by adopting mechanisms that allow for public dialogue prior to
publication, and streamline the guidance development process so the agency can routinely produce a draft within
180 days.
With the final guidance, publish nonbinding high-level summary and discussion of the comments submitted on the
document.
If the guidance is not finalized for more than a year, deem the guidance as revoked, as removed from the agency’s
website and as not consulted by agency employees unless FDA publishes a further notice indicating its intent to
continue to pursue finalizing the draft, in which case the document can remain active for another year. FDA
should also confirm that under existing law, the agency should not cite draft guidance.
Ensure a guidance document reflects the view of the entire agency, and not just a particular center, unless FDA
identifies specific reasons why the guidance should apply more narrowly.
Adopt a set of metrics to evaluate the agency’s effectiveness in developing high-quality guidance documents in a
timely fashion.
Senate health committee chair Lamar Alexander (R-TN) and Sen. Richard Burr (R-NC) briefly address the topic in a
white paper on their innovation initiative in January.
“When the agency puts forward policy in these draft guidances it can have unintended consequences,” the white
paper says. “If such guidances are not quickly finalized or withdrawn, those policies become all that sponsors and the
public have on which to rely as FDA’s most current understanding of an issue.”
At last week’s health committee hearing on the innovation initiative, Sen. Johnny Isakson (R-GA) criticized FDA for
relying on around 170 draft guidances that have yet to be finalized, referencing a letter FDA sent to the committee.
“[I]t is true investment follows certainty and certainty follows regulatory processes that work where industry knows
what it’s doing, and I find it troubling that FDA has so much difficulty working through the regulatory process,” he said,
adding that FDA seems to be relying on draft guidances and untitled warning letters.
In its letter, FDA says agency staff interpret how the statute relates to a specific issue regardless of whether a guidance document has been drafted, adding that it may look like FDA staff are relying on a draft guidance when staff reach
the same result, but it does not mean they are applying the draft guidance. — Erin Durkin
FDA Sets Up Expedited Review Pathway For Certain Breakthrough Drugs
FDA codified an expedited review pathway for breakthrough-designated drugs in a manual of policies and procedures (MAPP) released this week, instructing FDA review teams to act at least one month before the Prescription Drug
User Fee Act (PDUFA) goal date for these applications. FDA confirmed it had been informally putting drugs through
expedited review for several months, according to an industry attorney.
In order for a breakthrough drug to be considered for an expedited review, it must have these qualifications:
Preliminary review of results from clinical trials indicate the drug has demonstrated substantial improvement over
existing therapies.
The marketing application is designated as a priority review.
The review team must have determined that a first cycle approval is likely.
Factors that may influence a decision to conduct an expedited review, even if other criteria for such a review are met,
include: other public health priorities make it so the necessary resources are not available; an advisory committee meeting
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FDA Week - www.InsideHealthPolicy.com - March 20, 2015
is needed for reasons such as clinical trial results or safety issues; and unanticipated safety issues are identified that
require a risk evaluation and mitigation strategy.
A review team may determine that an expedited review is no longer appropriate for a drug if unexpected application
deficiencies are found; the marketing application is poor; the sponsor fails to engage in collaborative communications;
there is a need to hold an AC meeting; unanticipated review issues arise; or the review team experiences an unexpected
shift in work priorities or team staffing.
According to Hyman, Phelps & McNamara attorney, Alexander Varond, there has been evidence from recent approvals of breakthrough therapy-designated products that FDA has been operating under accelerated review timelines. In an
FDA Law Blog Friday (March 13), he said FDA confirmed this and stated that it has been “informally instituting a policy to
expedite the review of certain breakthrough therapy-designated applications for the past several months.” — Erin Durkin
Group Says Draft Undermines FDA Authority . . . begins on page one
on the draft guidance, or 0.62 percent, support FDA’s proposal. These comments came from pharmaceutical companies
and their trade associations, along with a single academic. The group says that FDA only posted 79 of the 1,782 comments it received on the agency’s website as of March 6.
“As predicted, the proposal’s few supporters primarily are industry companies and their associations, all of which
would benefit from being allowed and encouraged to sell more of their products by making them seem safer than the FDA
has judged them to be,” said Sidney Wolfe, founder and senior adviser for Public Citizen’s Health Research Group.
FDA states in its June 6, 2014 draft guidance that it “will not object” to drug companies providing doctors
with new information showing a lower risk for a product than what is published on the approved label. The guidance
says companies can give doctors peer-reviewed studies published in a scientific or medical journal, and that a company’s
representatives may discuss the new risk information with doctors. The information must be reprinted from scientific and
medical journals and include a cover sheet that details the design, critical findings, methodology and limitations of the
study as well as a statement that says FDA has not reviewed the data and lists any financial interests or affiliations
between the study authors and the manufacturer.
The agency argues that such information would be helpful to health care practitioners. “FDA recognizes that the safety
profile of a drug evolves throughout the lifecycle as the extent of exposure to the product increases and that it can be helpful for
health care practitioners to receive significant new risk information about an approved product in timely manner,” states the
draft guidance. “FDA anticipates that the earliest distribution of new risk information will generally involve distribution of
recently published studies, as opposed to textbooks or clinical practice guidelines. Accordingly, FDA is providing guidance for
firms that choose to distribute new risk information in the form of reprint or digital copy of a published study.”
But Public Citizen notes that nearly all who commented on the draft disagreed with FDA’s stance.
“Public Citizen again urges you to immediately withdraw this reckless and justifiably embarrassing proposed
Guidance, because it seriously undermines FDA authority. Its main supporters are drug companies and their associations,
all of which would benefit from being allowed and encouraged to sell more drugs by making them seem safer than FDA
has judged them to be. Ninety-nine percent of commenters strongly disagreed with the FDA’s proposed Guidance — and
only 1 percent supported it,” the letter says.
Instead the group says that when post-market evidence shows a reduction in risk of a drug, that data should
be submitted to the FDA, which should then be tasked with determining whether to change the label.
Wolfe had also suggested such an alternative in an October article published in JAMA Internal Medicine.
“When evidence supports a reduction in the risk associated with the use of a prescription drug or biological product, the
manufacturer should send the evidence to the FDA, state the basis for the reduction in risk, and request a labeling change. …
The fact that such promotion, if incorporated into either the labeling or the advertising for a drug, might violate FDA laws and
regulations highlights the substantial, risky change in drug promotion that the draft Guidance would allow,” Wolfe wrote.
Public Citizen includes in its letter to FDA last week a number of comments opposing the draft guidance, and also
excerpts on the other side from a detailed set of comments from a working group of two law firms that represents a
number of high profile drug companies saying the FDA’s proposal is still too restrictive.
The Medical Working Information Group (MWIG) of the Ropes & Gray and Sidney Austin law firms says the
proposal is vague in a way that will restrict protected First Amendment speech by drug manufacturers. The MWIG —
whose members include Allergan, Inc., Amgen, Inc., Bayer Healthcare Pharmaceuticals, Inc., Boehringer Ingelheim
Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., GlaxoSmihKline LLC, Johnson & Johnson, Novartis
Pharmaceutical Corporation, Norvo Nordisk, Inc., Pfizer, Inc. Purdue Pharma L.P. and Sanofi US — says the restrictions
on what type of information can be given to doctors are too stringent and will be difficult to meet.
“Rather than prohibiting the dissemination of publications that fail to satisfy these safe harbor requirements, the
Agency should instead affirmatively permit manufacturers to distribute a broader range of studies and analyses so long as
the design and limitations are clearly disclosed ,” MWIG says in its comments on FDA draft document, titled “Guidance
FDA Week - www.InsideHealthPolicy.com - March 20, 2015
11
for Industry: Distributing Scientific and Medical Publications on Risk Information for Approved Prescription Drugs and
Biological Products — Recommended Practices.”
But the drug industry has conversely argued that only FDA should be responsible for updating drug labels
when new safety risks emerge. A joint proposal sent to FDA in November by the Generic Pharmaceutical Association
(GPhA) and the Pharmaceutical Researchers and Manufacturers of America (PhRMA) says the agency, not drug makers,
should be responsible for mandating generic labeling changes regarding new safety information on adverse events found
post-market. The comments were in the context of the industry groups’ opposition to an FDA proposed rule requiring that
generic drug makers be required to change the labels independently without FDA review of data. FDA will hold a public
meeting on the proposed rule on March 27. — Todd Allen Wilson
FDA Seeks To Harmonize Device Post-Market Risk Efforts With Industry
The agency will hold a public meeting April 21 to engage with stakeholders on ways industry and FDA can work
together to better manage medical device risk once products are on the market. The meeting comes as FDA moves to rely
more on post-market data collection, and as House and Senate lawmakers eye legislative ways to speed marketing of
medical devices through greater reliance on post-market trials.
Both FDA and industry want to harmonize they way they assess risk in postmarket quality and safety situations,
including with product defects, failures, faults, or shortages, and any resulting harm, the agency says in a March 19
Federal Register notice announcing the meeting.
Currently, industry and FDA may respond differently when a postmarket safety or quality issue comes up, FDA notes.
“During this analysis, firms typically look for changes from their preproduction risk analysis to their postmarket experience and apply or update their risk management plan as appropriate,” FDA says. “In contrast, FDA responds to the same
issue by assessing information submitted in the firm’s premarket submission and may consider other information such as
information collected during an inspection when it is available.”
The all-day event will focus on managing risk, instead of eliminating it altogether, because full elimination is
unfeasible, FDA says. The agency says it hopes to nail down principles with industry stakeholders to “ help bridge
differences in understanding when conducting risk assessments.”
The agencies held meetings last year with a working group of the Association of Advancement of Medical Instrumentation to create a draft list of risk principles and factors to consider in analyzing postmarket risk. At the meeting next
month, those draft principles and factors will be presented for discussion.
FDA specifically asks for feedback on the following:
“What factors are important to take into account when conducting risk assessments of safety and quality
issues that occur with marketed medical devices? What principles best guide the risk assessment process to
assure timely, consistent, and optimal results?
Are there improvements that FDA and stakeholders could make to enhance risk assessments in recall and
shortage situations with medical devices?
Are there specific activities or issues related to postmarket quality, safety, or compliance activities where
approaches used by FDA and industry currently differ enough to create confusion or delay or limit appropriate public health actions? Please identify them.
In which activities and areas of postmarket quality, compliance, and safety would more detailed policies or
guidance be most useful?”
FDA says it hopes the meeting will offer an opportunity for “a collaborative discussion on postmarket risk principles
and factors assessing risk when changes occur due to postmarket quality and safety situations.”
The public workshop will be held on April 21, from 8:30 a.m. to 5 p.m. at FDA’s White Oak Campus. — David Hood
Brand-Name Drug Industry Touts Data To Back Up 12-Year Biologics Demand
Waikoloa, HAWAII — U.S. brand-name drug companies are trying to persuade Trans-Pacific Partnership (TPP)
countries to support the U.S. proposal for 12 years of data exclusivity for biologic drugs by arguing that this would not
delay the introduction to market of follow-on versions of these medicines known as biosimilars.
They have compiled preliminary data to show that biosimilars went on the market an average of 18-24 years after the
originator drug in TPP countries that have a special “pathway” for approving biosimilars, according to Joe Damond,
senior vice president for international affairs at the Biotechnology Industry Organization (BIO).
Even in TPP countries that do not have such a special pathway, biosimilars took on average 11.9 years to enter the
market from the date the original biologic drug was approved, Damond said at a March 9 event for intellectual property
(IP) negotiators here that was organized by the U.S. Chamber of Commerce.
Damond noted that four TPP countries have special pathways for approving biosimilars — Australia, New Zealand,
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FDA Week - www.InsideHealthPolicy.com - March 20, 2015
Canada and Malaysia — that are in accordance with World Health Organization guidelines.
Some of them have explicitly modeled their systems on the approach used by the European Medicines Agency
(EMA), but none of these countries has ever approved a biosimilar before EMA. This implies a significant delay in
bringing biosimilars to the market in these TPP nations, as the EU provides 10 years of combined data exclusivity and
marketing exclusivity, which can be extended by one additional year for new uses.
Damond emphasized that this data, which the industry plans to release soon, does not reflect merely a sample but is
an evaluation of every single marketing approval for a biosimilar that has ever occurred in a TPP country. The data was
compiled by IMS Health, a consulting group.
Biologics include most new cancer drugs and many medicines for other illnesses such as rheumatoid arthritis and
multiple sclerosis, along with many vaccines.
Asked why it is so crucial for the brand-name industry to secure 12 years of data exclusivity for biologics in TPP if
biosimilars are already taking that much time or longer to enter the market, Damond cited two reasons. The first is to
create “legal certainty” for investors in biotechnology companies that competing biosimilars would not be put on the
market for 12 years. The second is to ensure that countries do not try to cut corners in order to speed up the marketing
approval of a biosimilar, he said.
He noted that historical data showing that biosimilars typically were not introduced until more than 12 years after the
approval of the original biologic would likely not be enough to convince venture capitalists to invest in a biotechnology
company.
“I could take this data to a venture capital company and say ‘hey look, no one’s going to launch,’ and they’d say ‘well
are you sure no one can launch,’ and [I would say] ‘no but no one historically has,’” Damond said. “They’re not going to
invest in a company unless there’s legal certainty on the intellectual property rights.”
On his second point, he said some countries might diverge from the historical data because they are rushing
biosimilars to the market at the risk of harming patient safety and the drug’s efficacy, as well as undermining the incentives for research.
Biosimilars take longer than traditional generic drugs to come to market because they require a larger investment and
longer time for development, and regulatory agencies are treating them with special care due to their complexity, according to Damond.
He noted that the cost of production for biosimilar drugs is $75-250 million, and that it usually takes 7-8 years to get
manufacturing up and running and to conduct clinical trials. This contrasts with typical generic drugs, which can be
developed for $1-4 million in a matter of months, he said.
Clinical trials are not required for generic drugs since they are chemically equivalent to the originator drug; generic
companies can simply rely on the test data submitted by the brand-name manufacturer after the data exclusivity term has
run out.
In general, the Chamber panel discussion focused on rebutting key arguments of TPP critics that the U.S. demand on
biologics data protection and other IP issues would hinder access to affordable medicine and lead to poor health outcomes.
Philip Stevens, executive director of the for-profit Emerging Markets Health Network, made the general argument
that free trade agreements can improve health outcomes by creating economic growth that results in higher incomes for
patients. He said there was a growing body of evidence that showed an “important relationship” between open markets
and better health care.
He also fought back against the notion that the TPP IP provisions would drive up medicine costs in developing
countries by arguing that the majority of drugs prescribed in these nations are ones whose patents have expired.
In addition, he contended that the TPP would have no impact on the flexibilities available to countries under the 2001 Doha
Declaration for TRIPS and Public Health, which include the ability to issue compulsory licenses for production of a given drug
in third countries. This means AIDS programs in countries like Vietnam, Malaysia and Peru would not be affected, he argued.
That assessment conflicts with the findings of a draft study by U.S. and Australian academics, which found that
access to anti-retroviral drugs used to treat HIV would be roughly cut in half in Vietnam if the provisions in the current
U.S. IP proposal were the basis for a final TPP deal. Some critics have also charged that the U.S. demands on biologics in
TPP would drive up the cost for Australia’s health system by millions of dollars and delay the availability of biosimilars.
Another panelist, Andrew Spiegel, executive director of the Global Colon Cancer Association, expressed support for
the U.S. proposal in TPP for 12 years of data protection for biologics, saying strong IP protection is needed in order
create the incentives for brand-name drug companies to develop life-saving medicines.
“And that is why we are supportive of this trade agreement, because we feel that the 12 years of IP protection has
proven in the U.S., at least, to spur investment in the biotechnology arena,” he said.
Spiegel’s organization joined 107 other health and trade groups in sending an undated letter to the administration
expressing their support for “maintaining strong incentives for U.S. medical innovators in domestic and international
trade policy including 12 years of data protection for biologics,” without mentioning TPP specifically.
Also participating in the event was Patrick Kilbride, executive director of the Chamber’s Global IP Center.
But critics of stringent IP protections attacked the credibility of both Spiegel and Stevens, arguing that they have
conflicts of interest because their groups are funded in whole or in part by brand-name drug companies.
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13
On its website, the Global Colon Cancer Association lists as its sponsors BIO, the Pharmaceutical Research and
Manufacturers of America (PhRMA), and Genentech, a biotech company.
The Emerging Markets Health Network is a project of the Institute for Democracy and Economic Affairs (IDEAS), a
market-oriented think tank in Malaysia. A 2013 financial statement posted on the website of IDEAS showed the group received
contributions of roughly $83,000 from PhRMA’s international affairs division and $18,000 from Pfizer’s Malaysia subsidiary
during that year. At the same time, it listed the cost of the Emerging Markets Health Network project as $76,800 in 2013.
A brand-name drug industry source fought back, blasting these critics for latching on to the funding issue rather than
responding to the substance of the panelists’ arguments. — Inside U.S. Trade
Senate Budget Resolution Calls For Repeal Of Medical Device Tax
The Senate budget resolution released Wednesday (March 18) calls for repealing the ACA’s 2.3 percent excise tax on
medical device manufacturers, to the applause of Senate Finance Committee Chairman Orrin Hatch (R-UT) and Sen. Pat
Toomey (R-PA). Both senators have led efforts to repeal the device tax provision.
“Obamacare’s onerous medical device tax has harmed healthcare innovation, stifled job creation, and burdened the
delivery of quality patient care,” Hatch said. “Efforts to repeal this tax have received overwhelming bipartisan support in the
past, and I couldn’t be more pleased Chairman Enzi has included the repeal of this disastrous tax in his budget. It is time to end
this tax so that more resources can be devoted to healthcare innovation — not to the coffers of Obamacare.” — Erin Durkin
Public Citizen Jumps In Fight to Require Gluten Labeling In Drugs
Public Citizen filed a complaint in the U.S. District Court for the District of Columbia Tuesday (March 17) asking
the court to order FDA to take action on eliminating gluten from medications or requiring drug makers to declare the
ingredient in its labeling, following up on a citizen petition originally filed an individual in 2008.
The nonprofit consumer advocacy group says it filed the lawsuit because FDA has delayed a decision on the citizen
petition for seven years. The 2008 petition says people diagnosed with celiac disease must have detailed information on
products, including drugs — the disease causes patients to experience severe adverse reactions to gluten if consumed
regularly. Because gluten is used in a variety of medications as an inactive ingredient to “bind” other substances, people
with the disease need to monitor medications carefully. Currently, FDA does not require drug makers to declare gluten
products used in medications.
Michael Weber, of Rochester, New York, first filed the petition to the agency in 2008 and it garnered more than 70
comments. Three years later, FDA requested comments whether gluten should be banned altogether from use in the
manufacturing of drugs.
“Mr. Weber and millions of others have waited far too long for the FDA to act,” said Katie Einspanier, Public
Citizen’s attorney handling the case. “While the FDA drags its feet, millions who suffer from celiac disease will continue
to be injured or risk injury every time they take medications that contain wheat gluten. The absence of rules to address
wheat gluten in prescription medications has serious and ongoing public health implications.”
The group also argues that the issue becomes more complex when brand-name drugs use different “binders” and
inactive ingredients than their generic drug counterparts, or generics use different ingredients than another generic versions
of the same product. FDA regulations require generic drug companies to have congruent labels to their brand-name equivalents,
but if brand drug makers are not required to list gluten as an ingredient, generic drugs would not be required either.
“Although nearly seven years have passed since Mr. Weber filed his petition, the FDA has neither granted nor denied
the petition, and has taken no action to ban the use of gluten in pharmaceuticals or to require additional labeling. Therefore, Mr. Weber seeks a declaration that the FDA has acted unlawfully by withholding action on his petition and an order
requiring the FDA to act,” Einspanier wrote in court documents. — David Hood
House Passes Bill Preventing Drug Launch Delays Due To DEA Scheduling
The House this week passed bipartisan legislation that expedites the scheduling of new chemical entities to address
concerns that FDA-approved drugs have faced marketing delays because they must wait for Drug Enforcement Administration (DEA) scheduling decisions.
The language in the Improving Regulatory Transparency for New Medical Therapies Act, passed by voice vote
Monday (March 16), would require DEA to schedule new drugs 90 days after they are approved or when it receives the
FDA’s scheduling recommendation.
An industry attorney noted that this iteration of the bill was significantly different from prior versions of the legislation.
“The final version amends not only the [Controlled Substances Act], but also the [Food, Drug & Cosmetic] Act and
patent term extension laws,” says John Gilbert, an attorney for Hyman, Phelps & McNamara in an FDA Law Blog. “In
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doing so, this legislation more directly addresses the crux of the issue, ensuring that companies do not lose patent or nonpatent exclusivity on newly approved drugs because of drug scheduling delays.”
The bill was sponsored by Rep. Joe Pitts (R-PA) and carries the names of Reps. Frank Pallone (D-NJ) and Gene
Green (D-TX).
“I’m pleased to see the House pass my bipartisan bill to cut red tape and get critical drugs to patients faster,” said
Pitts. “Patients shouldn’t have to wait months or years for the Drug Enforcement Agency to reach the same conclusion as
the Food and Drug Administration. The bill also helps clear the way for important clinical trials to start sooner.” — Erin Durkin
OIG Fines Sandoz $12.6M For Misrepresenting Drug Pricing Data To HHS
The drug giant Sandoz will pay HHS more than $12 million for allegedly misrepresenting drug pricing to data to the
Medicare program, the HHS Office of Inspector General announced Monday (March 16). The settlement is the largest
ever under the OIG’s drug pricing reporting civil monetary penalty.
According to the announcement, Sandoz misrepresented average sales prices for two years in reporting to CMS, in
both its “accuracy” and timeliness. In 2011, The OIG fined Sandoz $230,000 for late reporting.
The OIG said its actions against Novartis, owner of Sandoz, will be a warning shot to other companies to submit both
accurate and timely reports in the future. “Sandoz’s misrepresentations undermined the integrity of the Medicare Part B
drug pricing system; we will continue to penalize manufacturers that misrepresent or fail to timely file the required
information,” said OIG Chief Counsel Gregory Demske in a statement. — David Hood
Court Rules In Sandoz’s Favor . . . begins on page one
The decision ends a contentious legal battle involving the first FDA-approved biosimilar — Sandoz’s filgrastim
biosimilar of Amgen’s Neupogen — where Amgen brought suit against Sandoz in October saying the biosimilar sponsor
violated the Biologics Price Competition and Innovation Act by not sharing its manufacturing information. Sandoz’s
product received approval earlier this month.
The law sets forth a process where a biosimilar applicant and the reference product sponsor “shall” participate in a
series of exchanges regarding potential disputes over patent validity and infringement. If both companies comply with
these disclosures and negotiations, neither company may bring a declaratory action regarding patent validity, enforceability or infringement against the other until the biosimilar applicant provides notice of its upcoming first commercial
marketing, according to court documents.
The court noted that the statute repeatedly used the word “shall,” to describe the companies’ obligations under the
patent dance exchange. Amgen argues that Sandoz’s decisions not to engage in the patent exchange “amount to unlawful
transgressions of mandatory requirements.”
However, U.S. District Judge Richard Seeborg states: “While such phrasing lends support to Amgen’s reading,
Sandoz’s overall interpretation of the statute’s plain language is more persuasive... First, that an action ‘shall’ be taken
does not imply it is mandatory in all contexts. It is fair to read subsection (l) to demand that, if both parties wish to take
advantage of its disclosure procedures, then they ‘shall’ follow the prescribed procedures; in other words, these procedures are ‘required’ where the parties elect to take advantage of their benefits, and may be taken away when parties
‘fail.’”
Congress took the additional step in the law to add that an applicant’s failure to disclose information regarding a
potentially infringed patent is immediately actionable, Seeborg continues, making it clear that such a dispute is “ripe for
adjudication.”
Seeborg also points out that the process could take up to 230 days just to commence patent litigation, and he said an
applicant may conclude that the disclosure and negotiation process would “introduce needless communications and
delay,” and in such cases, may opt out of the process and instead commence litigation immediately.
Amgen had also complained to the court that Sandoz intended to launch its product immediately upon receiving FDA
approval, rather than waiting until at least 180 days afterward.
The BPCIA provision states that an applicant “shall provide notice to the reference product sponsor not later than
180 days before the date of the first commercial marketing of the biological product licensed under subsection (k).”
The court says that Amgen “makes too much of the phrase,” and says that Amgen’s reading would add an unconditional extra six months of market exclusivity onto the 12 years reference product sponsors already have.
“Had Congress intended to make the exclusivity period twelve and one-half years, it could not have chosen a more
convoluted method of doing so,” writes Seeborg. “Moreover, Congress presumably could have been far more explicit had
it intended for infringement suits to commence only once a biosimilar receives FDA approval. It was, therefore, not
wrongful for Sandoz to give Amgen its 180 days’ notice prior to first commercial marketing...in July 2014, in advance of
receiving FDA approval.”
The court says that Amgen’s motion for preliminary injunction, which would place the parties “where they would
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have stood had Sandoz fully complied with the BPCIA as Amgen interprets it,” also fails. Seeborg says that Amgen does
not carry its burden to demonstrate that irreparable harm will result in the absence of injunctive relief.
“Not only are such harms at best highly speculative; they are based on the as-yet unproven premise that Sandoz has
infringed a valid patent belonging to Amgen,” says the court. “While Amgen has averred infringement of its ‘427 patent and
argues that Sandoz’s biosimilar filgrastim has the potential to infringe some four hundred more...it has not raised these contentions for a disposition at this juncture...As the twelve-year exclusivity period for Neupogen long ago expired, there exists no
substantive bar to market entry for Sandoz’s biosimilar filgrastim — and, consequently, no basis on which Amgen is entitled to
injunctive relief or other remedies for disadvantages it may suffer due to market competition from Sandoz.” — Erin Durkin
GNC Puts Supplements Back On Market, Says Four Tests Refute AG’s Data
GNC said it is putting its dietary supplements back on the shelves after a third-party found the products, which were
deemed adulterated by New York Attorney General Eric Schneiderman last month, are safe and pure. At the same time,
dietary supplement lobby groups released a white paper challenging the AG’s reliance on DNA barcoding and calling for
Schneiderman to release his test details.
The supplement industry giant, which had already conducted tests during the production process, after production
and prior to distribution, asked an independent third party to retest the supplements in response to the AG’s inquiry. “In
all four instances, the testing showed that the GNC Herbal Plus products meet all requirements for safety, quality, purity
and proper labeling on these products,” the company said in a release. “These results clearly and conclusively demonstrate that the Company’s products contain all herbal extracts listed on their respective labels and are compliant with
regulations prior to distribution.”
Frank Davis, director of regulatory affairs for Regulatory Compliance Associates, reviewed the results by GNC
and found the supplements to be unadulterated. “Testing of the specified lots of products by accepted and reliable
methods, and with reference to limits promulgated by the USP (United States Pharmacopeia), supports that these lots are
not adulterated or mislabeled, contrary to the allegations of the NY AG letter,” Davis said in a press release.
Schneiderman’s office declined to comment on both the white paper and the statement by GNC.
Schneiderman recently sent cease and desist letters to GNC, Target, Walmart, and Walgreens for allegedly selling
herbal supplement products in the state that in some cases didn’t include labeled ingredients or were otherwise adulterated. Schneiderman’s office used a DNA barcoding test that purportedly showed that only 21 percent of the test results
from store-brand herbal supplements had verified DNA from the plants listed on the products’ labels. The industry white
paper and GNC say barcoding test results, which are at the fulcrum of the debate, are unfounded.
FDA said that it does not routinely use the test to verify dietary supplements (see related story). The agency does not
conduct premarket review of supplements, but only observes reported adverse events and then takes necessary action
against companies.
The white paper, produced by the American Herbal Products Association, Consumer Healthcare Products Association, Council for Responsible Nutrition and United Natural Products Alliance, explains the general uses for DNA
barcoding in forensic science and for identifying people, not plants. “Its use as a routine tool for authentication of
botanical (herbal) dietary supplements is relatively recent and far less established,” the paper says. “As a result, a general
lack of understanding exists—even by those who claim to perform DNA testing— of the complexities of the methods,
especially as they relate to finished dietary supplement products containing botanical extracts.”
That “lack of awareness,” the paper says, has resulted in the misuse and misinterpretation of the testing results. The
paper maintains DNA barcoding is one of several DNA testing methods and claims it is not the most appropriate for
testing finished products. The groups offered a strong critique of Schneiderman’s barcoding test, saying that though there
are little details on the tests performed, information gleaned from the results show five conclusions.
“If specific DNA authentication methods were not used targeting short DNA fragments, a high rate of false negative
results would have been highly probable,” the paper says. The paper argues that identifying species is extremely difficult
and the method cannot be adapted from its use in reptilian biology to authenticating botanical products. The groups also
say that critical components missing from the attorney general’s study are processes of retesting for similar results so as to
not produce false positives.
Lastly, the white paper states that reference gene sequences for species under investigation by the attorney general
are not publicly available. “Most of the species under investigation by the NY AG cannot be accurately identified without
a proprietary database of reference sequences, as several of the species under investigation—including St. John’s wort
and Echinacea—do not have publicly available reference sequences from the genes necessary to identify them,” the
groups say.
Last month, Dietary Supplement Caucus Chairmen Orrin Hatch (R-UT) and Martin Heinrich (D-NM) sent a
letter to FDA asking if the DNA barcoding test is condoned by the agency. The pair received a response Wednesday
(March 18) from FDA saying it has not reviewed Schneiderman’s test results or methodology and taking a neutral
stance on the issue. — David Hood
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